共查询到20条相似文献,搜索用时 15 毫秒
1.
Joachim Mittendorf Prof. Dr. Stefan Weigand Dr. Cristina Alonso‐Alija Dr. Erwin Bischoff Dr. Achim Feurer Dr. Michael Gerisch Dr. Armin Kern Dr. Andreas Knorr Dr. Dieter Lang Dr. Klaus Muenter Dr. Martin Radtke Dr. Hartmut Schirok Dr. Karl‐Heinz Schlemmer Dr. Elke Stahl Dr. Alexander Straub Dr. Frank Wunder Dr. Johannes‐Peter Stasch Dr. 《ChemMedChem》2009,4(5):693-693
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Dr. Lars Bärfacker Dr. Alexander Kuhl Prof. Dr. Alexander Hillisch Dr. Rolf Grosser Dr. Santiago Figueroa‐Pérez Dr. Heike Heckroth Adam Nitsche Dr. Jens‐Kerim Ergüden Dr. Heike Gielen‐Haertwig Dr. Karl‐Heinz Schlemmer Prof. Dr. Joachim Mittendorf Dr. Holger Paulsen Dr. Johannes Platzek Dr. Peter Kolkhof 《ChemMedChem》2012,7(8):1301-1301
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L Bärfacker A Kuhl A Hillisch R Grosser S Figueroa-Pérez H Heckroth A Nitsche JK Ergüden H Gielen-Haertwig KH Schlemmer J Mittendorf H Paulsen J Platzek P Kolkhof 《ChemMedChem》2012,7(8):1385-1403
Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano‐1,4‐dihydropyridines that were identified by high‐throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94‐8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial. 相似文献
4.
Daniel Fleischmann Manuela Harloff Sara Maslanka Figueroa Jens Schlossmann Achim Goepferich 《International journal of molecular sciences》2021,22(5)
Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular hyperproliferation. These pathological effects are in part caused by an impaired functionality of soluble guanylate cyclase (sGC) and a consequentially reduced synthesis of anti-fibrotic messenger 3′,5′-cyclic guanosine monophosphate (cGMP). Bay 58-2667 (cinaciguat) is able to re-activate defective sGC; however, the drug suffers from poor bioavailability and its systemic administration is linked to adverse events such as severe hypotension, which can hamper the therapeutic effect. In this study, cinaciguat was therefore efficiently encapsulated into virus-mimetic nanoparticles (NPs) that are able to specifically target renal mesangial cells and therefore increase the intracellular drug accumulation. NP-assisted drug delivery thereby increased in vitro potency of cinaciguat-induced sGC stabilization and activation, as well as the related downstream signaling 4- to 5-fold. Additionally, administration of drug-loaded NPs provided a considerable suppression of the non-canonical transforming growth factor β (TGF-β) signaling pathway and the resulting pro-fibrotic remodeling by 50–100%, making the system a promising tool for a more refined therapy of DN and other related kidney pathologies. 相似文献
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Hartmut Schirok Dr. Raimund Kast Dr. Santiago Figueroa‐Pérez Dr. Samir Bennabi Dr. Mark J. Gnoth Dr. Achim Feurer Dr. Heike Heckroth Dr. Michael Thutewohl Dr. Holger Paulsen Dr. Andreas Knorr Dr. Joachim Hütter Dr. Mario Lobell Dr. Klaus Münter Dr. Volker Geiß Dr. Heimo Ehmke Prof. Dr. Dieter Lang Dr. Martin Radtke Dr. Joachim Mittendorf Dr. Johannes‐Peter Stasch Dr. 《ChemMedChem》2008,3(12):1797-1797
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Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Claudia Sorbi Dr. Rossella Gallesi Michela Buccioni Dr. Gabriella Marucci Prof. Carla De Stefani Dr. Antonio Cilia Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(2):196-203
A selective 5‐HT 1A receptor agonist : A new series of ligands acting at 5‐HT1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5‐HT1A/α1D>150), and represents a new 5‐HT1A agonist chemotype.
8.
Diaryl‐Substituted Azolylthioacetamides: Inhibitor Discovery of New Delhi Metallo‐β‐Lactamase‐1 (NDM‐1) 下载免费PDF全文
Yi‐Lin Zhang Prof. Ke‐Wu Yang Ya‐Jun Zhou Alecander E. LaCuran Prof. Peter Oelschlaeger Prof. Michael W. Crowder 《ChemMedChem》2014,9(11):2445-2448
The emergence and spread of antibiotic‐resistant pathogens is a global public health problem. Metallo‐β‐lactamases (MβLs) such as New Delhi MβL‐1 (NDM‐1) are principle contributors to the emergence of resistance because of their ability to hydrolyze almost all known β‐lactam antibiotics including penicillins, cephalosporins, and carbapenems. A clinical inhibitor of MBLs has not yet been found. In this study we developed eighteen new diaryl‐substituted azolylthioacetamides and found all of them to be inhibitors of the MβL L1 from Stenotrophomonas maltophilia (Ki<2 μM ), thirteen to be mixed inhibitors of NDM‐1 (Ki<7 μM ), and four to be broad‐spectrum inhibitors of all four tested MβLs CcrA from Bacteroides fragilis, NDM‐1 and ImiS from Aeromonas veronii, and L1 (Ki<52 μM ), which are representative of the B1a, B1b, B2, and B3 subclasses, respectively. Docking studies revealed that the azolylthioacetamides, which have the broadest inhibitory activity, coordinate to the ZnII ion(s) preferentially via the triazole moiety, while other moieties interact mostly with the conserved active site residues Lys224 (CcrA, NDM‐1, and ImiS) or Ser221 (L1). 相似文献
9.
Xiangdong Su Dr. Fabienne Pradaux‐Caggiano Dr. Mark P. Thomas Dr. Michelle W. Y. Szeto Dr. Heather A. Halem Dr. Michael D. Culler Dr. Nigel Vicker Dr. Barry V. L. Potter Prof. 《ChemMedChem》2010,5(7):1026-1044
11β‐Hydroxysteroid dehydrogenases (11β‐HSDs) are key enzymes regulating the pre‐receptor metabolism of glucocorticoid hormones. The modulation of 11β‐HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue‐specific glucocorticoid action by regulating 11β‐HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11β‐HSD1. The most active compounds identified ( 52 , 62 , 72 , 92 , 103 and 104 ) display potent inhibition of 11β‐HSD1 with IC50 values in the 50–70 nM range. Compound 72 also proved to be metabolically stable when incubated with human liver microsomes. Furthermore, compound 72 showed very weak inhibitory activity for human cytochrome P450 enzymes and is therefore a candidate for in vivo studies. Comparison of the publicly available X‐ray crystal structures of human 11β‐HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor. 相似文献
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Discovery and SAR of Novel 2,3‐Dihydroimidazo[1,2‐c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80‐6946) 下载免费PDF全文
Dr. William J. Scott Dr. Martin F. Hentemann Dr. R. Bruce Rowley Cathy O. Bull Dr. Susan Jenkins Ann M. Bullion Jeffrey Johnson Anikó Redman Dr. Arthur H. Robbins William Esler Dr. R. Paul Fracasso Timothy Garrison Dr. Mark Hamilton Dr. Martin Michels Dr. Jill E. Wood Dean P. Wilkie Hong Xiao Dr. Joan Levy Enrico Stasik Dr. Ningshu Liu Dr. Martina Schaefer Prof. Dr. Michael Brands Dr. Julien Lefranc 《ChemMedChem》2016,11(14):1517-1530
The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3‐dihydroimidazo[1,2‐c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate for the treatment of solid and hematological tumors are described. 相似文献
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The copolymers of (Z)‐4‐oxo‐4‐phenoxyl‐2‐butenoic acid with styrene (PSt/OPBA) and their macromolecular luminous lanthanide complexes (Ln‐PSt/OPBA) have been synthesized and characterized by means of GPC, elemental analysis, FTIR, X‐ray powder diffraction, spectral analysis, and thermal analysis. The IR studies showed that the carboxylic groups on the side chain of the polymer were coordinated to lanthanide ions by bidentate manner. However, the ethereal oxygen, instead of carbonyl, also bonded to the central lanthanide ions, which was an intriguing phenomenon for ester‐coordinated complexes. X‐ray diffraction experiments revealed that these PSt/OPBA copolymers were amorphous, but Ln‐PSt/OPBA were crystalline, in which the complex Eu‐Lc belonged to a high symmetric structure of orthorhombic quadratic system, with a = 10.59 ± 0.02 Å, c = 8.02 ± 0.01 Å; c/a = 0.763. In addition, the value δ (the number of free carboxylic groups) in Ln‐PSt/OPBA complexes increased with the decreasing mole ratio of styrene in the copolymers, while it decreased with increasing pH values of the solution. Eu3+ and Tb3+ complexes exhibited characteristic fluorescence with comparatively high brightness and good monochromaticity, and the fluorescence intensity was enhanced with increasing the content of lanthanide up to around 18 wt % without typical fluorescence concentration quenching behavior in the solid state. So using polymers as a matrix, Ln‐PSt/OPBA are likely to provide new materials that possess specific properties and desired features. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012 相似文献
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The relative energies of the three possible isomers of 2,5‐dibenzylidenecyclopentanone and of 2,6‐dibenzylidenecyclohexanone were calculated using Mechanics, MOPAC, and MOPAC with CI. The calculated lowest energy isomer of each compound agrees with known spectroscopic and crystallographic data. This work shows that the “SCF‐CI” calculations previously reported on 2,5‐dibenzylidenecyclopentanone do not predict the actual structure of the compound and should not be used to predict the structure of the corresponding polymer. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 2255–2257, 1999 相似文献
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Boris A. Trofimov Tatyana E. Glotova Dmitrii A. Shabalin Marina Yu. Dvorko Igor A. Ushakov Elena Yu. Schmidt Anton V. Kuzmin Al'bina I. Mikhaleva 《Advanced Synthesis \u0026amp; Catalysis》2013,355(8):1535-1539
Acetylenes undergo the [4+2] cycloaddition to 3,6‐di(pyrrol‐2‐yl)‐1,2,4,5‐tetrazine in the potassium hydroxide/dimethyl sulfoxide or potassium tert‐butoxide/dimethyl sulfoxide systems (80 °C, 2.5–4 h) to afford (after extrusion of the nitrogen molecule from the intermediate) 3,6‐di(pyrrol‐2‐yl)pyridazines in up to 73% yield, while under non‐catalytic conditions this reaction does not take place. This unusual result substantially extends the scope of synthetic application and mechanistic diversity of the Diels–Alder reaction. The step‐wise mechanisms involving the formation of [OH/tetrazine]− or [t‐BuO/tetrazine]− anionic intermediate complexes or cycloaddition of tetrazine to the acetylide anion are considered. 相似文献
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Poly(2‐acrylamido glycolic acid‐co‐2‐acrylamido‐2‐methyl‐1‐propane sulfonic acid) [P(AGA‐co‐APSA)] was synthesized by radical polymerization in an aqueous solution. The water‐soluble polymer, containing secondary amide, hydroxyl, carboxylic, and sulfonic acid groups, was investigated, in view of their metal‐ion‐binding properties, as a polychelatogen with the liquid‐phase polymer‐based retention technique under different experimental conditions. The investigated metal ions were Ag+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Pb2+, and Cr3+, and these were studied at pHs 3, 5, and 7. P(AGA‐co‐APSA) showed efficient retention of all metal ions at the pHs studied, with a minimum of 60% for Co(II) at pH 3 and a maximum close to 100% at pH 7 for all metal ions. The maximum retention capacity (n metal ion/n polymer) ranged from 0.22 for Cd2+ to 0.34 for Ag+. The antibacterial activity of Ag+, Cu2+, Zn2+, and Cd2+ polymer–metal complexes was studied, and P(AGA‐co‐APSA)–Cd2+ presented selective antibacterial activity for Staphylococcus aureus with a minimum inhibitory concentration of 2 μg/mL. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009 相似文献
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Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia 下载免费PDF全文
Dr. Anthony J. Roecker Swati P. Mercer John D. Schreier Dr. Christopher D. Cox Dr. Mark E. Fraley Justin T. Steen Wei Lemaire Joseph G. Bruno C. Meacham Harrell Susan L. Garson Dr. Anthony L. Gotter Steven V. Fox Joanne Stevens Dr. Pamela L. Tannenbaum Dr. Thomayant Prueksaritanont Dr. Tamara D. Cabalu Dr. Donghui Cui Joyce Stellabott Dr. George D. Hartman Dr. Steven D. Young Dr. Christopher J. Winrow Dr. John J. Renger Dr. Paul J. Coleman 《ChemMedChem》2014,9(2):311-322
The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1R and OX2R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1R or OX2R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models. 相似文献
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Discovery and Characterization of 2‐(Cyclopropanesulfonamido)‐N‐(2‐ethoxyphenyl)benzamide,ML382: a Potent and Selective Positive Allosteric Modulator of MrgX1 下载免费PDF全文
Wandong Wen Dr. Yan Wang Zhe Li Dr. Pang‐Yen Tseng Dr. Owen B. McManus Dr. Meng Wu Dr. Min Li Prof. Craig W. Lindsley Prof. Xinzhong Dong Prof. Corey R. Hopkins 《ChemMedChem》2015,10(1):57-61
Previous studies have shown that the activation of mouse MrgC11, a G‐protein‐coupled receptor, by its peptide ligand BAM8‐22 can inhibit chronic pain. A large‐scale screen has been carried out to isolate small‐molecule allosteric agonists of MrgX1, the human homologue of MrgC11. The goal of this study is to improve the efficacy and potency of positive allosteric modulators (PAMs) with therapeutic implications in combating chronic pain. Herein we report an iterative parallel synthesis effort and a structure–activity relationship study of a series of arylsulfonamides which led to the discovery of the first PAM of MrgX1, ML382. 相似文献
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Yemanlall Lochee Dhanjay Jhurry Archana Bhaw‐Luximon Afksendiyos Kalangos 《Polymer International》2010,59(9):1310-1318
The synthesis and detailed characterization of racemic 3‐methyl‐1,4‐dioxan‐2‐one (3‐MeDX) are reported. The bulk ring‐opening polymerization of 3‐MeDX, to yield a poly(ester‐ether) meant for biomedical applications, in the presence of various initiators such as tin(II) octanoate, tin(II) octanoate/n‐butyl alcohol, aluminium tris‐isopropoxide and an aluminium Schiff base complex (HAPENAlOiPr) under varying experimental conditions is here detailed for the first time. Polymerization kinetics were investigated and compared with those of 1,4‐dioxan‐2‐one. The studies reveal that the rate of polymerization of 3‐MeDX is less than that of 1,4‐dioxan‐2‐one. Experimental conditions to achieve relatively high molar masses have been established. Thermodynamic parameters such as enthalpy and entropy of 3‐MeDX polymerization as well as ceiling temperature have been determined. Poly(D ,L ‐3‐MeDX) is found to possess a much lower ceiling temperature than poly(1,4‐dioxan‐2‐one). Poly(D ,L ‐3‐MeDX) was characterized using NMR spectroscopy, matrix‐assisted laser desorption ionization mass spectrometry, size exclusion chromatography and differential scanning calorimetry. This polymer is an amorphous material with a glass transition temperature of about ?20 °C. Copyright © 2010 Society of Chemical Industry 相似文献
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Poly[(R,S)‐3‐hydroxybutyrate] oligomers containing dihyroxyl (PHB‐diol), dicarboxylic acid (PHB‐diacid) and hydroxyl‐carboxylic acid (a‐PHB) end functionalities were obtained by the anionic polymerization of β‐butyrolacton (β‐BL). Ring opening anionic polymerization of β‐BL was initiated by a complex of 18‐Crown‐6 with γ‐hydroxybutyric acid sodium salts (for PHB‐diol and a‐PHB) or succinic acid disodium salt (for PHB‐diacid). Dihydroxyl functionalization was formed by the termination of polymerization with bromo‐ethanol or bromo‐decanol while the others were done by protonation. Hydroxyl and/or carboxylic acid functionalized PHB oligomers with ceric salts were used to initiate the polymerization of methylmethacrylate (MMA). PHB‐b‐PMMA block copolymers obtained by this way were purified by fractional precipitation and characterized using 1H‐NMR and 13C‐NMR, gel permeation chromatography (GPC), and thermal analysis (DSC and TGA) techniques. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 965–973, 2002 相似文献
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UV‐Triggered Optical Response and Oxygen Scavenging Ability of a Water‐Soluble Poly(N,N‐dimethylacrylamide‐co‐2‐vinylbenzylanthraquinone) Copolymer 下载免费PDF全文
A vinyl‐modified anthraquinone (AQ) derivative (Vinyl‐AQ) is synthesized through a palladium‐mediated Suzuki coupling reaction between vinylphenylboronic acid and 2‐chloromethylanthraquinone and, subsequently, copolymerized with N,N‐dimethylacrylamide (DMAM) through free radical copolymerization in organic solvent. The chemical structure of the resulting water‐soluble copolymer, P(DMAM‐co‐AQ), is verified using techniques such as proton nuclear magnetic resonance, attenuated total reflection‐infrared spectroscopy, thermogravimetric analysis, and UV–vis spectroscopy. The evolution of the oxygen scavenging abilities of aqueous P(DMAM‐co‐AQ) solutions after UV irradiation is monitored as a function of UV irradiation time, concentration of AQ moieties, and pH. The copolymer is proved an effective UV‐triggered oxygen scavenger, leading to dissolved oxygen contents below 1 ppm for the optimized experimental conditions. This behavior is related with the appearance of novel chemical species with interesting optical properties, as suggested by the respective evolution of the UV–vis absorption and photoluminescence spectra after UV irradiation. 相似文献